Many hormones and neurotransmitters regulate biological functions via specific receptor proteins existing on the cell membrane. Most of such receptor proteins achieve intracellular signaling via the activation of coupled guanosine triphosphate-binding proteins (hereinafter abbreviated as “G proteins”) . Thus, the receptor proteins are collectively called “G protein-coupled receptor proteins”, or “seven-transmembrane receptor proteins”, due to their common structure comprising seven transmembrane domains.
G protein-coupled receptor proteins exist on the surface of living cells and various functional cells in organs. The receptor proteins play exceedingly important roles as targets of various molecules, for example, such as hormones, neurotransmitters, and physiologically active substances, that regulate the functions of the cells and organs.
An exemplary pathway wherein a hormone or neurotransmitter and a G protein-coupled receptor regulate biological function includes the hypothalamic pituitary system. In this system, the secretion of pituitary hormones from pituitary is regulated by the function of hypothalamic hormones, and the pituitary hormones released into blood regulate the functions of target cells and organs. For example, functions important for the living body, such as maintenance of homeostasis, and development and/or growth of genital system and individuals, are regulated via the pathway.
Representative hypothalamic hormones include thyrotropin-releasing hormone (TRH) , corticotropin-releasing factor (CRF) , growth hormone-releasing factor (GRF) , and somatostatin; and pituitary hormones include thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) , follicle stimulating hormone (FSH) , luteinizing hormone (LH) , prolactin, growth hormone, oxytocin, and vasopressin. In particular the secretion of pituitary hormones is regulated by a positive or negative feedback mechanism by hypothalamic hormones and peripheral hormones secreted from target endocrine gland.
These hormones and their receptors are known to be present not only in the hypothalamic pituitary system but also are widely distributed in the brain. The hormones and their receptors are also similarly distributed in peripheral tissues and are believed to perform important functions.
For example, pancreas plays an important role in sugar metabolism via the secretion of glucagon and insulin in addition to digestive juice. Insulin is secreted from β cells of the pancreas, which secretion is mainly promoted by glucose. However, various types of receptors are present on the β cells, and, in addition to glucose, insulin secretion is known to be controlled by various factors, such as peptide hormones (galanin, somatostatin, gastrin, secretin, gastric inhibitory polypeptide, glucagon, etc.), sugars (mannose, etc.), amino acids, and neurotransmitters.
In digestive organs, such as the stomach and small intestine, food digestion and absorption are performed by the secretion of various digestive juices under the control of multiple hormones, hormone-like substances, neurotransmitters or physiologically active substances including gastrin, secretin, glucagon, gastrin-releasing peptide, vasoactive intestinal peptide, acetylcholine, noradrenaline, and serotonin. The secretion of these substances is believed to be regulated by receptors corresponding to each substance existing in stomach, small intestine, and so on.
Similarly, in the cardiovascular system and respiratory system such as the heart and lung, the contraction and relaxation of cardiac muscle and vascular smooth muscle, the control of blood pressure, and such are strictly performed under the regulation of neurotransmitters, hormones, physiologically active substances, etc.
As described above, in peripheral tissues, such as brain and pituitary, receptor proteins of various hormones and neurotransmitters exist and play important roles in regulating the functions of the tissues. Thus, G protein-coupled receptor proteins have been greatly attracting attention as targets to develop pharmaceuticals.
Previously reported G protein-coupled receptor proteins include: muscarinic acetylcholine receptors M1, M2, M3, and M4 (Peralta, E. G. et al., EMBO J. 6, 3923–3929 (1987)); muscarinic acetylcholine receptor M5 (Bonner, T. I. et al., Neuron 1, 403–410 (1988)); adenosine receptor A1 (Libert, F. et al., Science 244, 569–572 (1989)); α1A adrenoreceptor (Bruno, J. F. et al., Biochem. Biophys. Res. Commun. 179, 1485–1490 (1991)); β1 adrenoreceptor (Frielle, T. et al., Proc. Natl. Acad. Sci. USA 84, 7920–7924 (1987)); angiotensin receptor AT1 (Takayanagi, R. et al., Biochem. Biophys. Res. Commun. 183, 910–916 (1992)); endothelin receptor ETA (Adachi, M. et al., Biochem. Biophys. Res. Commun. 180, 1265–1272 (1991)); gonadotropin-releasing factor receptor (Kaker, S. S. et al., Biochem. Biophys. Res. Commun. 189, 289–295 (1992)) histamine receptor H2 (Ruat, M. et al., Proc. Natl. Acad. Sci. USA 87, 1658–1672 (1992)); neuropeptide Y receptor Y1 (Larhammar, D. et al., J. Biol. Chem. 267, 10935–10938(1992)); interleukin 8 receptor IL8RA (Holmes, W. E. et al., Science 2563, 1278–1280 (1991)) ; dopamine receptor D1 (Mahan, L. C. et al., Proc. Natl. Acad. Sci. USA 87, 2196–2200 (1990)); metabolic glutamate receptor mGluR1 (Masu, M. et al., Nature 349, 760–765 (1991)); somatostatin receptor SS1 (Yamada, Y. et al., Proc. Natl. Acad. Sci. USA 89, 251–255 (1992)), etc. (see, Watson, S. and Arkinstall, S., The G-Protein Linked Receptor FactsBook, Academic Press (1994)). Furthermore, already developed pharmaceuticals targeting a G protein-coupled receptor protein include: terazosin hydrochloride (antihypertensive agent, α1 adrenoreceptor antagonist) , atenolol (antiarrhythmic agent, β1 adrenoreceptor antagonist), dicyclomine hydrochloride (anticonvulsant, acetylcholine receptor antagonist) ranitidine hydrochloride (peptic ulcer agent, histamine receptor H2 antagonist) , trazodone hydrochloride (antidepressant, serotonin receptor 5-HT1B antagonist), buprenorphine hydrochloride (analgesic, opioid receptor κ agonist), etc. (see, Stadel. J. M. et al., Trends Pharm. Sci. 18, 430–437 (1997); Pharmaceutical Catalogue, 5th ed., Jiho, Inc.).